Cancer accounts for one-fifth of the total mortality in the United States, and is the second leading cause of death. Cancer is typically characterized by the uncontrolled division of a population of cells. This uncontrolled division may involve blood cells, such as various types of lymphomas, or cells that aggregate in or are native to a particular tissue or organ, e.g., solid tumors, such as secondary or primary tumors of the breast, lung, liver, esophagus, stomach, intestines, brain, bone, or prostate.
A variety of treatment modalities have been proposed for cancer therapy. One such treatment modality relates to the use of particular enzymes to inhibit growth of cancer cells. One such enzyme known in the art is urease, an enzyme that catalyzes the hydrolysis of urea into carbon dioxide and ammonia. More specifically, urease catalyzes the hydrolysis of urea to produce ammonia and carbamate, the carbamate produced is subsequently degraded by spontaneous hydrolysis to produce another ammonia and carbonic acid. In this regard, urease activity tends to increase the pH of the local environment in which it is as it produces ammonia, as it is a basic molecule.
The concept of using antibodies to target tumor associated antigens in the treatment of cancer has been appreciated for some time (Herlyn et. al., (1980) Cancer Research 40, 717). However, as to urease, the toxic component is the alkaline environment produced by enzymatic degradation of urea. In such a case, the antibody employed need only to have a high binding affinity to the corresponding antigen. Although therapeutic antibodies can be used with the urease, ongoing clinical trials employ only a high affinity antibody fragment. This approach provides for several unique considerations including the fact that urease is an exceptionally large enzyme while the antibody fragments are significantly smaller. To address possible steric hinderence arising from the size of the urease, it is conventional to use multiple copies of the non-human antibody fragment.
As multiple copies of these fragments are used to ensure proper binding, limitations as to the inclusion of other components on the antibody. Moreover, as binding sites on the antibody fragment may be limited, binding of each antibody fragment to the urease is through a single tether. Still further, while immunogenicity of the antibody fragment appears to be minimal, a non-immunogenic approach would eliminate even the smallest likelihood of an adverse immune response or the need to co-administer an immunosuppressive agent.